Endometrial cancer is the most common gynecologic malignancy In the US. Most endometrial cancers are sporadic. However, some patients have an inherited cancer susceptibility, usually due to mutation in a DNA mismatch repair gene. These women have Lynch syndrome. They are at much Increased risk for colorectal and other malignancies, as are their family members. Identification of endometrial cancer patients with Lynch syndrome is important to the proband and her family. Intensified cancer surveillance is required for individuals with Lynch syndrome mutations. In particular, colonic surveillance reduces cancer burden. Although health professionals are increasingly aware of Lynch syndrome, most endometrial cancer probands with Lynch syndrome likely go undetected. Molecular screening strategies should help to address this deficiency, but at present, the best approach is unknown. The importance of DNA mismatch repair abnormalities in endometrial cancer is further evidenced by the high frequency of acquired (somatic) defects, most frequently epigenetic silencing of the MLH1 repair gene. Our group has shown inherited variation in the MLH1 gene itself is associated with risk for abnormal methylation and gene silencing, and have data suggesting specific environmental factors contribute to risk. The aims for this project address important questions regarding mismatch repair abnormalities in endometrial cancer. (1) Develop of a molecular screening regimen to compliment family history risk assessment for the detection of Lynch syndrome. >3,000 endometrial cancers from the GOG-210 study will be evaluated using MSI, IHC, promoter methylation and gene sequencing. (2) Better estimate the frequency of Lynch syndrome among endometrial cancer patients and determine the clinicopathologic significance of mismatch repair defects. Detailed clinical, medical and family history and epidemiologic data from the GOG-210 study will be correlated with molecular phenotypes. (3) Further refine the relationship between inherited variation in the MLHI DNA repair gene and epigenetic silencing of MLHI in sporadic endometrial cancer. A nested case- control study will define key genetic and environmental factor interactions. The work proposed will improve identification of Lynch syndrome and with that reduce cancer burden, and better define key genetic and environmental factor leading to somatic (acquired) inactivation of mismatch repair in endometrial cancers. RELEVANCE (See instructions): The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.